In the United States, the incidence of ischemic or nonischemic heart failure (HF) is increasing. Once HF reaches end-stage, treatment options decrease. Up to 150,000 HF patients could benefit from a transplant, but only about 2000 donor hearts per year are available in the United States. Therefore, left ventricular assist devices (LVADs) have been developed as bridges to transplantation and as destination therapy. In some patients, LVAD therapy has led to ventricular recovery, obviating the need for transplantation or destination therapy. A promising new method for treating severe HF is regeneration of infarcted myocardium by stem cells, especially mesenchymal stem cells (MSCs). Found in bone marrow and adipose tissue, MSCs can differentiate into multiple cell types and can favorably affect revascularization and cardiac remodeling. The hypothesis of this proposed Stage 1 C-TRIP application is that stem cell therapy will benefit LVAD recipients with ischemic or nonischemic chronic HF. Three specific aims are proposed: 1) We will determine the safety and efficacy of NOGA mapping and transendocardial and transepicardial injection of allogeneic mesenchymal precursor cells (MFCs) in an LVAD-bearing sheep model of ischemic cardiomyopathy. 2) We will compare transendocardial and direct-surface transepicardial injection techniques and identify the most effective method of injecting allogeneic MFCs. 3) We will develop the final clinical trial protocol, data management tools, and IND application for clinical trials in Stage 2. Bridge-to-transplant patients provide a unique opportunity for studying the mechanisms of myogenesis and angiogenesis after stem cell therapy. Direct injection of MFCs into the heart at LVAD implantation allows post-transplant histologic and immunologic study of the effects of stem cell therapy in the explanted heart, clarifying which therapies will best enhance regional blood flow and myocardial function. Combined stem cell and LVAD therapy is an innovative approach that may enhance ventricular recovery, allowing more patients to undergo device removal without transplantation. This first phase of the C-TRIP application may facilitate translation of this promising new intervention into a clinical trial. RELEVANCE (See instructions): A successful result would represent a major advancement in stem cell and LVAD therapy and could eventually lead to more effective treatments for thousands of patients with end-stage ischemic or nonischemic heart disease who have no other options for treatment.